PROJECT SUMMARY Peripheral inflammation is an important and modifiable risk factor for Alzheimer?s disease (AD), and epidemiologic studies suggest that mid-life metabolic syndrome, obesity, and hypertension are inter-related health care conditions that increase the risk of age-related neurodegenerative disorders, particularly AD. The mechanistic links between these systemic disorders and neurodegeneration are poorly understood, but may be the key to developing effective anti-AD therapeutics. Recently, in experiments in germ-free mice, we have shown that bacterially-induced redox events occur in enteric ganglion cells and lamina propria phagocytic cells, suggesting that chronic exposure or abnormal microbiota community structurecould result in redox stress in mucosal cells, oxidative inactivation of proteolytic machinery in these cells, and consequent generation and propagation of misfolded/aggregated proteins (e.g. alpha-synuclein). The novel overarching hypothesis of this proposal is that diminished gut barrier function and translocation of bacteria and their components associated with aging or an obesogenic diet cause chronic inflammation and redox stress, which may contribute to impaired gut immune function, and dysregulated proteostasis. We hypothesize these events trigger neuroinflammation and compromise vulnerable brain neuronal populations in a way that increases risk for neurodegeneration in susceptible brain regions such as the locus coeruleus (LC), the main noradrenergic center that degenerates early in age-related neurodegenerative diseases such as AD and PD. To test this hypothesis, we have assembled an interdisciplinary team of experts in gut immunology, neuroinflammation, and neurodegeneration to investigate the following integrated hypotheses using several novel mouse models and germ-free (or gnotobiotic) facilities: 1) Bacterial-induced inflammation and redox stress influence immune cell activation and proteostasis in the mucosa and enteric nervous system; 2) Nrf2 protects against inflammatory and redox stress on proteostasis in noradrenergic neurons in vitro and in vivo; and 3) Noradrenergic neurons in the locus coeruleus display vulnerability to disrupted proteostasis that can be further enhanced by gut dysbiosis and gut inflammation. Successful completion of the proposed studies will provide new and potentially paradigm-shifting mechanistic information on how gut microbiota and diet-induced chronic peripheral inflammation contribute to ENS dysfunction and early degeneration of noradrenergic brain centers affected in AD.